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1.
medRxiv ; 2023 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-38014089

RESUMO

Acne vulgaris is a common skin disease that affects >85% of teenage young adults among which >8% develop severe lesions that leaves permanent scars. Genetic heritability studies of acne in twin cohorts have estimated that the heritability for acne is 80%. Previous genome-wide association studies (GWAS) have identified 50 genetic loci associated with increased risk of developing acne when compared to healthy individuals. However only a few studies have investigated genetic association with disease severity. GWAS of disease progression may provide a more effective approach to unveil potential disease modifying therapeutic targets. Here, we performed a multi-ethnic GWAS analysis to capture disease severity in acne patients by using individuals with normal acne as a control. Our cohort consists of a total of 2,956 participants, including 290 severe acne cases and 930 normal acne controls from FinnGen, and 522 cases and 1,214 controls from BioVU. We also performed mendelian randomization (MR), colocalization analyses and transcriptome-wide association study (TWAS) to identify putative causal genes. Lastly, we performed gene-set enrichment analysis using MAGMA to implicate biological pathways that drive disease severity in Acne. We identified two new loci associated with acne severity at the genome-wide significance level, six novel associated genes by MR, colocalization and TWAS analyses, including genes CDC7, SLC7A1, ADAM23, TTLL10, CDK20 and DNAJA4 , and 5 novel pathways by MAGMA analyses. Our study suggests that the etiologies of acne susceptibility and severity have limited overlap, with only 26% of known acne risk loci presenting nominal association with acne severity and none of the novel severity associated genes reported as associated with acne risk in previous GWAS.

2.
Gulf J Oncolog ; 1(41): 54-61, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36804159

RESUMO

BACKGROUND: Lung cancer is the most frequent cause of cancer-related deaths worldwide. The discovery of acquired genetic alterations in the epidermal growth factor receptor (EGFR) gene involved in growth factor receptor signaling, has changed the way these cancers are diagnosed and treated. EGFR is more frequent in Asian, females, and non-smokers. Data regarding its prevalence in the Arab World remains limited. This paper aims at reviewing the data available for the prevalence of this mutation in the Arab patient population and comparing it with other international series. METHODS: PubMed and ASCO databases were used to conduct a literature search and 18 relevant studies were included. RESULTS: Overall, 1775 patients with non-small cell lung cancer (NSCLC) were included in this analysis. 15.7% had an EGFR mutation and 56% of the mutated patients were females. 66% of EGFR mutated patients were nonsmokers. Exon 19 and exon 21 were, respectively the most and the second most prevalent mutation. CONCLUSIONS: The EGFR mutation frequency in Middle East and African patients lies between the frequency of Europe and North America. Like global data, it is more prevalent in females and non-smokers.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Feminino , Humanos , Masculino , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mundo Árabe , Mutação , Receptores ErbB/genética
3.
Haematologica ; 108(7): 1920-1933, 2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-36373248

RESUMO

Leg ulcers are a major complication of sickle cell disease (SCD). They are particularly challenging to treat and innovative therapies are needed. We previously showed that the healing of SCD ulcers is delayed because of decreased angiogenesis. During pregnancy, fetal microchimeric cells (FMC) transferred to the mother are recruited to maternal wounds and improve angiogenesis. After delivery, FMC persist in maternal bone marrow for decades. Here, we investigated whether fetal cells could also improve SCD ulcers in the post-partum setting. We found that skin healing was similarly improved in post-partum mice and in pregnant mice, through increased proliferation and angiogenesis. In a SCD mouse model that recapitulates refractory SCD ulcers, we showed that the ulcers of post-partum SCD mice healed more quickly than those of virgin mice. This was associated with the recruitment of fetal cells in maternal wounds where they harbored markers of leukocytes and endothelial cells. In a retrospective cohort of SCD patients, using several parameters we found that SCD women who had ever had a baby had less of a burden related to leg ulcers compared to nulliparous women. Taken together, these results indicate that healing capacities of FMC are maintained long after delivery and may be exploited to promote wound healing in post-partum SCD patients.


Assuntos
Anemia Falciforme , Úlcera da Perna , Gravidez , Feminino , Camundongos , Animais , Úlcera/complicações , Células Endoteliais , Estudos Retrospectivos , Cicatrização , Úlcera da Perna/complicações , Úlcera da Perna/terapia , Anemia Falciforme/complicações
4.
BMC Nephrol ; 23(1): 344, 2022 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-36303122

RESUMO

BACKGROUND: Hemodialysis patients are followed by routine laboratory testing. There is uncertainty whether these tests always lead to a change in decision-making. This study aims to discover the number of yearly interventions/changes in prescription based on these tests and depict the group of patients who would benefit from reduced or increased laboratory blood tests. METHODS: This is a multi-center retrospective study that included patients on hemodialysis for more than one year. Laboratory data collected included yearly average of hemoglobin, urea reduction ratio (URR), serum phosphate, calcium, potassium, parathormone (PTH), ferritin and transferrin saturation (TSAT); changes in prescription of erythropoietin-stimulating agents (ESAs), intravenous (IV) iron, alfacalcidol, phosphate binders and dialysis parameters were retrieved from medical records. A multivariate regression analysis assessed factors associated with high number of interventions. RESULTS: A total of 210 hemodialysis patients were included: 62.4% males, 47.1% diabetics. Their median age was 72 (62,78.5) years. Their laboratory parameters were within KDIGO targets. The median number of yearly interventions was 5 (3,7) for ESAs, 4 (2,6) for IV iron, 1 (0,2.25) for phosphate binders, 0 (0,1) for alfacalcidol. Based on the multivariate analysis, patients with higher ferritin, frequent changes in ESA, more changes in alfacalcidol and higher PTH had higher number of prescription's changes in ESA, IV iron, phosphate binders and alfacalcidol respectively. CONCLUSION: While maintaining KDIGO targets, therapeutic interventions following routine laboratory testing did not exceed six times yearly for all parameters. This suggests that a reduced testing frequency in hemodialysis patients is possible without any impact on quality of care. A personalized approach remains safe for hemodialysis patients while reducing the cost. This is very relevant in low-resource settings and during economic crises and needs to be evaluated in prospective studies.


Assuntos
Anemia , Hematínicos , Falência Renal Crônica , Idoso , Feminino , Humanos , Masculino , Ferritinas , Hematínicos/uso terapêutico , Hemoglobinas/metabolismo , Ferro , Falência Renal Crônica/terapia , Fosfatos , Estudos Prospectivos , Diálise Renal , Estudos Retrospectivos , Pessoa de Meia-Idade
5.
Exp Dermatol ; 30(7): 988-994, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33969538

RESUMO

Neutrophil extracellular traps (NETs) are implicated in the pathogenesis of multiple inflammatory dermatoses. However, characterization of NETs in neutrophilic dermatoses was performed on very limited number of patients; this limitation precluded definitive conclusions. In this case series of 57 patients, we compared the amounts of neutrophils producing NETs in cutaneous lesions of different entities of neutrophilic dermatoses (17 with pyoderma gangrenosum, 37 with Sweet's syndrome and three with subcorneal pustular dermatosis). NETs were identified by double immunofluorescence on formalin-fixed paraffin-embedded skin biopsies using antibodies against elastase and citrullinated histone 3. Percentages of neutrophils showing NETs were high across all three entities (62.9% in PG, 48.5% in SS and 37.8% in subcorneal pustular dermatosis). The differences in mean percentages were significant between entities, with PG showing significantly superior percentage of NETs compared with SS. In our series, 15.8% of neutrophilic dermatoses were associated with malignancies, 10.5% with autoimmune diseases and 73.7% were idiopathic. Percentages of NETs were not statistically different between aetiologies. These findings suggest that NETs are abundantly produced in the various entities and different aetiologies of neutrophilic dermatoses. In comparison with SS, the superior percentage of NETs in PG is clinically mirrored in its greater ulceronecrotic nature.


Assuntos
Armadilhas Extracelulares , Neutrófilos/patologia , Dermatopatias Vesiculobolhosas/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pioderma Gangrenoso/patologia , Síndrome de Sweet/patologia , Adulto Jovem
6.
Int J Dermatol ; 60(6): 724-729, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33580883

RESUMO

BACKGROUND: Panniculitides are a heterogeneous group of inflammatory dermatoses involving the subcutaneous fatty tissue. Histologically, they are classified into septal and lobular panniculitis, according to the predominant localization of the inflammatory infiltrate. Neutrophils are frequently found in panniculitis, mainly at the early stages. Here, we investigated whether neutrophils contribute to various types of cutaneous panniculitis by releasing neutrophil extracellular traps (NETs). MATERIALS AND METHODS: Formalin-fixed paraffin-embedded skin biopsies from 25 patients with panniculitis were included in the study. Our cohort was divided into n = 10 erythema nodosum (septal panniculitis) and n = 15 lobular panniculitis, including n = 7 lupus panniculitis, n = 1 pancreatic panniculitis, n = 1 Weber-Christian disease, n = 1 deep fungal infection, n = 2 lipodermatosclerosis, and three cases did not have an identified etiology. The presence of neutrophils and NETs was assessed by double immunofluorescence using antibodies against elastase, a neutrophilic marker, and citrullinated histone 3, a marker of NETs. RESULTS: The mean percentages (±SEM) of elastase-positive neutrophils showing NETs were 44% ± 3% in erythema nodosum and 43% ± 7% in lobular panniculitis. The difference was not statistically significant and reflects the implication of NETs not only in severe scarring lobular panniculitis but also in benign non-scarring self-remitting reactive inflammation such as erythema nodosum. In tissues, NETs were located in the interlobular septa in erythema nodosum and in the inflamed fat lobules in lobular panniculitis. CONCLUSIONS: NETs are massively present in septal and lobular subtypes of panniculitides, suggesting their involvement in tissue damage.


Assuntos
Eritema Nodoso , Armadilhas Extracelulares , Paniculite de Lúpus Eritematoso , Paniculite , Humanos , Pele
7.
Low Urin Tract Symptoms ; 13(2): 286-290, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33283436

RESUMO

OBJECTIVES: The aim of this study was to assess the efficacy of laparoscopic transperitoneal pudendal decompression in the improvement of refractory lower urinary tract symptoms (LUTS) in young males presenting with clinical features of pudendal nerve entrapment with no known comorbidities that could explain their LUTS. METHODS: This is a prospective pilot study involving patients suffering from LUTS refractory to standard treatment and clinical features of pudendal nerve entrapment on physical examination. They underwent laparoscopic transperitoneal pudendal decompression. International Prostate Symptom Score (IPSS) and maximal flow (Qmax) on uroflowmetry were evaluated before and 3 months after the procedure. RESULTS: Five male patients aged 34 ± 4 years were recruited. The median IPSS differed significantly before and 3 months after the procedure (18 vs 8, P = .042); likewise, median Qmax differed significantly before and 3 months after the procedure (12 vs 18 mL/s, P = .042). CONCLUSION: Pudendal nerve entrapment syndrome should be considered as a main differential diagnosis for refractory LUTS in young males with no other comorbidities. When clinical features of pudendal nerve entrapment are present, laparoscopic transperitoneal pudendal decompression relieves LUTS in these young males.


Assuntos
Sintomas do Trato Urinário Inferior , Nervo Pudendo , Neuralgia do Pudendo , Humanos , Sintomas do Trato Urinário Inferior/etiologia , Sintomas do Trato Urinário Inferior/cirurgia , Masculino , Projetos Piloto , Estudos Prospectivos , Nervo Pudendo/cirurgia
8.
Acta Derm Venereol ; 100(17): adv00281, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-31663600

RESUMO

Formation of neutrophil extracellular traps has been implicated in autoimmunity. However, the presence and clinical relevance of neutrophil extracellular traps in immune-complex-mediated cutaneous small and medium vessel vasculitides has not been investigated. This study retrospectively analysed 72 patients with histology-proven hypersensitivity vasculitis (n = 21), IgA vasculitis (n = 22), urticarial vasculitis (n = 22), erythema elevatum diutinum (n = 3) and polyarteritis nodosa (n = 4). Neutrophil extracellular traps were detected in hypersensitivity vasculitis, IgA vasculitis, urticarial vasculitis and erythema elevatum diutinum, but not in polyarteritis nodosa lesions. Neutrophil extracellular traps were found around inflamed vessels, and their formation was highest early after the onset of vasculitis and decreased progressively thereafter. Neutrophil extracellular traps were strongly correlated with the histological severity of vasculitis and the production of reactive oxygen species. Both hypersensitivity vasculitis and IgA vasculitis showed significantly more neutrophil extracellular traps than did urticarial vasculitis, independent of the histological severity and duration of vasculitis. These results provide evidence on the implication of neutrophil extracellular traps in the early phases of immune-complex-mediated small vessel vasculitis.


Assuntos
Armadilhas Extracelulares , Vasculite Leucocitoclástica Cutânea , Vasculite , Humanos , Espécies Reativas de Oxigênio , Estudos Retrospectivos , Pele
9.
J Gastrointest Oncol ; 10(5): 859-868, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31602323

RESUMO

BACKGROUND: Ferrochelatase (FECH) is the last enzyme of the heme biosynthesis pathway. Deficiency in FECH was associated with many diseases, including protoporphyria. Correlation studies showed that variations of FECH expression was detected in human carcinomas and more specifically in colon cancer. Nevertheless, the potential role of FECH in colon cancer carcinogenesis in vitro was not depicted yet. METHODS: A small interfering RNA (siRNA) was used to knockdown FECH in human Caco-2 colon cancer cells. The effect of FECH down-regulation on the cellular proliferation, the migration and the expression of target genes was assessed in cancer cells and compared to human normal fibroblasts. RESULTS: Following FECH down-regulation, our results demonstrated that the proliferation of Caco-2 cells was not affected. Furthermore, the migration of cancer and normal cells was affected, only when an additional stress factor (H2O2) was applied to the medium. The expression of twist, snail, hypoxia induced factor (HIF-1α) and vascular endothelial growth factor (VEGF) was reduced in Caco-2 cells. Conversely, VEGF and HIF-1α expression were upregulated by up to 2 folds in control fibroblasts. Interestingly, the pro-carcinogenic long noncoding RNA (LncRNA) H19 was 70% down-regulated in Caco-2 cells upon FECH down regulation whereas no effect was observed in normal fibroblasts. CONCLUSIONS: In conclusion, we showed that loss of FECH is protective against colon cancer tumorigenesis in vitro and this effect could possibly be mediated through inhibition of H19.

10.
Exp Dermatol ; 28(11): 1348-1352, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31529548

RESUMO

Neutrophil extracellular traps (NETs) are implicated in the pathogenesis of systemic lupus erythematosus (SLE). However, little is known about the implication of NETs in cutaneous lupus. In this case series of 30 patients, we compared the amounts of neutrophils producing NETs in cutaneous lesions of different subtypes of lupus (5 with discoid lupus or DLE, 5 with subacute cutaneous lupus or SCLE, 11 with acute cutaneous SLE, 7 with lupus panniculitis and 2 with chilblains). Immunofluorescence was performed on formalin-fixed paraffin-embedded skin biopsies using antibodies against neutrophilic granules (elastase, myeloperoxidase, PR-3 proteins and citrullinated histone 3). Dihydroethidium staining was performed to detect reactive oxygen species (ROS), known inducers of NETs. NETs were detected in the different subtypes of cutaneous lupus as well as in cutaneous lesions of SLE. The amounts of neutrophils producing NETs were significantly higher in lupus panniculitis (49%), acute cutaneous SLE (41%) and DLE (32%), in comparison with SCLE (5%) and chilblains (0%). This suggests that NETs might be associated with more tissue damage and scarring. ROS were observed in the different cutaneous subtypes of lupus independent of NETs.


Assuntos
Armadilhas Extracelulares , Lúpus Eritematoso Cutâneo/imunologia , Neutrófilos/fisiologia , Humanos , Lúpus Eritematoso Cutâneo/patologia , Pele/imunologia , Pele/patologia
11.
J Infect Public Health ; 12(3): 438-441, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30213467

RESUMO

Concomitant disseminated herpes simplex virus (HSV) and varicella zoster virus (VZV) infection is a rare event. We describe a case of disseminated HSV and VZV infection in an 80-year-old patient many years after splenectomy for idiopathic thrombocytopenic purpura (ITP). This is the first case of disseminated HSV-1 and VZV infection with molecular evidence of the simultaneous presence of both viruses in two different body sites (the skin and cerebrospinal fluid). This adds to the three reports of patients developing cutaneous disseminated herpes zoster multiple years after splenectomy for ITP.


Assuntos
Herpes Simples/diagnóstico , Herpes Zoster/diagnóstico , Púrpura Trombocitopênica Idiopática , Idoso de 80 Anos ou mais , Coinfecção , Diagnóstico Diferencial , Evolução Fatal , Feminino , Herpes Simples/complicações , Herpes Zoster/complicações , Humanos
12.
J Dermatol Sci ; 92(2): 143-150, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30237006

RESUMO

BACKGROUND AND OBJECTIVES: Behçet's disease (BD) is a multi-system inflammatory disorder that can cause vasculitis. Here we questioned whether Neutrophils in BD cause vasculitis via releasing Neutrophil Extracellular Traps (NETs), a process called NETosis. METHODS: Circulating neutrophils were isolated from a cohort of Middle Eastern BD patients with an active disease and healthy volunteers. The percentage of NETs release was monitored in neutrophils stimulated or not with BD serum, and treated or not with Colchicine, Dexamethasone, Cl-amidine or N-Acetyl Cysteine (NAC). The mRNA expression levels of PAD4 (a key enzyme in NETosis) was also assessed. The effect of NETs on the proliferation and cell death of endothelial cells was investigated using an in vitro co-culture model. The presence of NETs in skin tissues of BD patients was examined using immunolabeling of NETs associated proteins. RESULTS: Circulating Neutrophils from BD patients were more prone to release NETs in vitro and expressed higher levels of PAD4 compared to healthy volunteers. Spontaneous NETs formation in BD neutrophils was inhibited by Colchicine and Dexamethasone, two drugs used to treat BD. NETs formation was also inhibited by Cl-amidine, a specific PAD4 inhibitor, and by NAC, a ROS inhibitor. Interestingly, serum from BD patients stimulated circulating neutrophils from healthy volunteers to release more NETs and increased their mRNA PAD4 expression. Moreover, endothelial cells cultured in the presence of NETs from BD patients showed a decrease in proliferation and an increase in apoptosis and cell death. Finally, NETosis was predominantly identified around affected blood vessels in biopsies of vasculitis from BD patients. CONCLUSION: Our results provide evidence on the implication of NETosis in the pathophysiology of BD especially in inducing vasculitis.


Assuntos
Apoptose/imunologia , Síndrome de Behçet/imunologia , Armadilhas Extracelulares/imunologia , Neutrófilos/metabolismo , Adulto , Síndrome de Behçet/sangue , Síndrome de Behçet/patologia , Biópsia , Estudos de Casos e Controles , Células Cultivadas , Técnicas de Cocultura , Células Endoteliais , Armadilhas Extracelulares/metabolismo , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Pele/irrigação sanguínea , Pele/citologia , Pele/imunologia , Pele/patologia
13.
Int J Dermatol ; 57(2): 162-170, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29231248

RESUMO

BACKGROUND: Mal de Meleda (MDM) is a rare inherited autosomal recessive genodermatosis characterized by palmoplantar keratoderma (PPK) with transgrediens and caused by mutations in the SLURP1 gene. Uncommonly, cutaneous tumors have been found at PPK sites in MDM patients. OBJECTIVE: To study a Middle Eastern family with MDM with both PPK and skin tumors. METHODS: We studied a Middle Eastern (Palestinian) family with clinical features of MDM and cutaneous tumors. Histopathological analysis was performed on biopsies from skin lesions found in the affected individuals. Direct sequencing of SLURP1 was performed in MDM affected members. In silico analysis of publicly available datasets was used to survey SLURP1 mRNA levels in normal and malignant tissues. Statistical analysis was performed in the R statistical language. RESULTS: Affected members from the Middle Eastern family displayed severe forms of PPK consistent with MDM. Histopathological analysis of the skin lesions revealed that the examined affected members exhibited skin squamous cell carcinomas (SCCs) and melanoma. Sequence analysis revealed homozygous SLURP1 mutations (c.82delT) in the affected members. Following analysis of various publicly available expression datasets, SLURP1 mRNA levels were found to be markedly elevated in tissues of epithelial lineage, relative to tissues of other lineages, and significantly suppressed in malignant tumors of epithelial lineage relative to normal or their premalignant counterparts. There was significant decrease in SLURP-1 expression in melanomas versus melanocytic nevi as well as a highly significant decrease in SLURP-1 expression in metastatic melanomas as compared to primary melanoma. CONCLUSION: Our study underscores cases of Middle Eastern MDM with SLURP1 mutations and skin malignancies at PPK sites. Our findings also highlight a plausible epithelial lineage-specific tumor suppressor role for the SLURP1 gene, as well as a role in the development and metastasis of melanoma and thus a potential molecular signature for melanoma.


Assuntos
Antígenos Ly/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Ceratodermia Palmar e Plantar/genética , Melanoma/genética , Nevo Pigmentado/genética , Neoplasias Cutâneas/genética , Ativador de Plasminogênio Tipo Uroquinase/genética , Adulto , Biomarcadores Tumorais/metabolismo , Bases de Dados Genéticas , Epitélio/metabolismo , Feminino , Expressão Gênica , Genes Supressores de Tumor , Homozigoto , Humanos , Ceratodermia Palmar e Plantar/patologia , Masculino , Melanoma/patologia , Melanoma/secundário , Pessoa de Meia-Idade , Mutação , Linhagem , RNA Mensageiro/metabolismo , Neoplasias Cutâneas/patologia
14.
Nat Commun ; 8: 15463, 2017 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-28516946

RESUMO

Foetal microchimeric cells (FMCs) traffic into maternal circulation during pregnancy and persist for decades after delivery. Upon maternal injury, FMCs migrate to affected sites where they participate in tissue healing. However, the specific signals regulating the trafficking of FMCs to injury sites had to be identified. Here we report that, in mice, a subset of FMCs implicated in tissue repair displays CD11b+ CD34+ CD31+ phenotype and highly express C-C chemokine receptor 2 (Ccr2). The Ccr2 ligand chemokine ligand 2 (Ccl2) enhances the recruitment of FMCs to maternal wounds where these cells transdifferentiate into endothelial cells and stimulate angiogenesis through Cxcl1 secretion. Ccl2 administration improves delayed maternal wound healing in pregnant and postpartum mice but never in virgin ones. This role of Ccl2/Ccr2 signalling opens new strategies for tissue repair through natural stem cell therapy, a concept that can be later applied to other types of maternal diseases.


Assuntos
Quimiocina CCL2/genética , Células Progenitoras Endoteliais/metabolismo , Neovascularização Fisiológica , Receptores CCR2/genética , Cicatrização/efeitos dos fármacos , Ferimentos não Penetrantes/genética , Animais , Antígenos CD34/genética , Antígenos CD34/metabolismo , Antígeno CD11b/genética , Antígeno CD11b/metabolismo , Quimiocina CCL2/metabolismo , Quimiocina CCL2/farmacologia , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Células Progenitoras Endoteliais/citologia , Feminino , Feto , Regulação da Expressão Gênica , Camundongos , Circulação Placentária/fisiologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Gravidez , Receptores CCR2/metabolismo , Transdução de Sinais , Cicatrização/genética , Ferimentos não Penetrantes/tratamento farmacológico , Ferimentos não Penetrantes/metabolismo , Ferimentos não Penetrantes/patologia
15.
Cell Stem Cell ; 20(2): 191-204.e5, 2017 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-27889319

RESUMO

Epithelial to mesenchymal transition (EMT) in cancer cells has been associated with metastasis, stemness, and resistance to therapy. Some tumors undergo EMT while others do not, which may reflect intrinsic properties of their cell of origin. However, this possibility is largely unexplored. By targeting the same oncogenic mutations to discrete skin compartments, we show that cell-type-specific chromatin and transcriptional states differentially prime tumors to EMT. Squamous cell carcinomas (SCCs) derived from interfollicular epidermis (IFE) are generally well differentiated, while hair follicle (HF) stem cell-derived SCCs frequently exhibit EMT, efficiently form secondary tumors, and possess increased metastatic potential. Transcriptional and epigenomic profiling revealed that IFE and HF tumor-initiating cells possess distinct chromatin landscapes and gene regulatory networks associated with tumorigenesis and EMT that correlate with accessibility of key epithelial and EMT transcription factor binding sites. These findings highlight the importance of chromatin states and transcriptional priming in dictating tumor phenotypes and EMT.


Assuntos
Carcinoma de Células Escamosas/patologia , Cromatina/metabolismo , Transição Epitelial-Mesenquimal , Células-Tronco Neoplásicas/patologia , Neoplasias Cutâneas/patologia , Animais , Sequência de Bases , Carcinogênese/patologia , Carcinoma de Células Escamosas/genética , Diferenciação Celular , Linhagem da Célula/genética , Células Clonais , Epigênese Genética , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Células HEK293 , Folículo Piloso/patologia , Humanos , Camundongos , Metástase Neoplásica , Fosfoproteínas/metabolismo , Proteínas Repressoras/metabolismo , Neoplasias Cutâneas/genética , Transativadores/metabolismo , Transcrição Gênica
16.
J Invest Dermatol ; 136(10): 2080-2089, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27262545

RESUMO

Impaired cutaneous wound healing is a social burden. It occurs as a consequence of glucocorticoid treatment in several pathologies. Glucocorticoids (GC) bind not only to the glucocorticoid receptor but also to the mineralocorticoid receptor (MR), both expressed by keratinocytes. In addition to its beneficial effects through the glucocorticoid receptor, GC exposure may lead to inappropriate MR occupancy. We hypothesized that dermatological use of MR antagonists (MRA) might be beneficial by overcoming the negative impact of GC treatment on pathological wounds. The potent GC clobetasol, applied as an ointment to mouse skin, or added to cultured human skin explants, induced delayed wound closure and outgrowth of epidermis with reduced proliferation of keratinocytes. Delayed wound re-epithelialization was rescued by local MRA application. Normal skin was unaffected by MRA. The benefit of MR blockade is explained by the increased expression of MR in clobetasol-treated mouse skin. Blockade of the epithelial sodium channel by phenamil also rescued cultured human skin explants from GC-impaired growth of the epidermis. MRA application over post-biopsy wounds of clobetasol-treated skin zones of healthy volunteers (from the Interest of Topical Spironolactone's Administration to Prevent Corticoid-induced Epidermal Atrophy clinical trial) also accelerated wound closure. In conclusion, we propose repositioning MRA for cutaneous application to improve delayed wound closure occurring in pathology.


Assuntos
Clobetasol/farmacologia , Glucocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Reepitelização/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Administração Cutânea , Amilorida/análogos & derivados , Amilorida/farmacologia , Animais , Clobetasol/administração & dosagem , Epiderme/efeitos dos fármacos , Epiderme/patologia , Glucocorticoides/administração & dosagem , Humanos , Queratinócitos/metabolismo , Camundongos , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Pomadas , Receptores de Mineralocorticoides/efeitos dos fármacos , Receptores de Mineralocorticoides/metabolismo , Pele/efeitos dos fármacos , Pele/patologia
17.
Annu Rev Pathol ; 11: 47-76, 2016 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-27193450

RESUMO

Different mechanisms contribute to intratumor heterogeneity, including genetic mutations, the microenvironment, and the existence of subpopulations of cancer cells with increased renewal capacity and the ability to recapitulate the heterogeneity found in primary tumors, which are referred to as cancer stem cells (CSCs). In this review, we discuss how the concept of CSCs has been defined, what assays are currently used to define the functional properties of CSCs, what intrinsic and extrinsic mechanisms regulate CSC functions, how plastic CSCs are, and the importance of epithelial-to-mesenchymal transition in conferring CSC properties. Finally, we discuss the mechanisms by which CSCs may resist medical therapy and contribute to tumor relapse.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/terapia , Células-Tronco Neoplásicas/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Animais , Humanos , Neoplasias/patologia , Células-Tronco Neoplásicas/patologia
18.
J Invest Dermatol ; 136(2): 497-506, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26967481

RESUMO

Leg ulcers are a major complication of sickle cell disease that occur in 2.5-40% of patients. Leg ulcers are responsible for frequent complications because they are often long-lasting and are highly resistant to therapy. Although their occurrence is associated with hyperhemolysis, the mechanisms underlying sickle cell ulcers remain poorly understood. In this study, we show that skin wound healing is severely altered in old SAD sickle cell mice but is normal in young animals, consistent with reports in humans. Alterations of wound healing were associated with impaired blood and lymphatic angiogenesis in the wound beds and poor endothelial progenitor cell mobilization from the bone marrow. CXCL12 secretion by keratinocytes and inflammatory cells was low in the wounds of SAD mice. Local therapy with endothelial progenitor cells or recombinant CXCL12 injections restored wound angiogenesis and rescued the healing defect together with mobilization of circulating endothelial progenitor cells. To our knowledge, this is a previously unreported study of the cellular and molecular mechanisms of sickle cell ulcers in a murine model that provides promising therapeutic perspectives for clinical trials.


Assuntos
Anemia Falciforme/complicações , Quimiocina CXCL12/metabolismo , Neovascularização Patológica/fisiopatologia , Úlcera Cutânea/patologia , Cicatrização/fisiologia , Anemia Falciforme/patologia , Animais , Proliferação de Células , Modelos Animais de Doenças , Células Progenitoras Endoteliais/transplante , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Úlcera Cutânea/fisiopatologia , Úlcera Cutânea/cirurgia , Transplante de Células-Tronco/métodos , Fatores de Tempo
20.
Nat Med ; 21(8): 946-54, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26168291

RESUMO

Mouse models of cancers are routinely used to study cancer biology. However, it remains unclear whether carcinogenesis in mice is driven by the same spectrum of genomic alterations found in humans. Here we conducted a comprehensive genomic analysis of 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced skin cancer, the most commonly used skin cancer model, which appears as benign papillomas that progress into squamous cell carcinomas (SCCs). We also studied genetically induced SCCs that expressed G12D mutant Kras (Kras G12D) but were deficient for p53. Using whole-exome sequencing, we uncovered a characteristic mutational signature of DMBA-induced SCCs. We found that the vast majority of DMBA-induced SCCs presented recurrent mutations in Hras, Kras or Rras2 and mutations in several additional putative oncogenes and tumor-suppressor genes. Similar genes were recurrently mutated in mouse and human SCCs that were from different organs or had been exposed to different carcinogens. Invasive SCCs, but not papillomas, presented substantial chromosomal aberrations, especially in DMBA-induced and genetically induced Trp53-mutated SCCs. Metastasis occurred through sequential spreading, with relatively few additional genetic events. This study provides a framework for future functional cancer genomic studies in mice.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Cutâneas/genética , 9,10-Dimetil-1,2-benzantraceno , Animais , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/patologia , Evolução Clonal , Exoma , Feminino , Genes ras , Genômica , Humanos , Camundongos , Mutação , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/patologia
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